Neisseria meningitidis (meningococcus) is a Gram negative human pathogen. It colonizes the pharynx, causing meningitis and, occasionally, septicemia in the absence of meningitis. It is closely related to N. gonorrhoeae, although one feature that clearly differentiates meningococcus is the presence of a polysaccharide capsule that is present in all pathogenic meningococci. Based on the organism's capsular polysaccharide, twelve serogroups of N. meningitidis have been identified (A, B, C, H, I, K, L, 29E, W135, X, Y and Z).
Serogroup A (‘MenA’) is most common cause of epidemic disease in sub-Saharan Africa. Serogroups B & C are responsible for the majority of cases in developed countries, with the remaining cases being caused by serogroups W135 & Y.
The vaccine utilizing the polysaccharide (PS) alone have relatively low immunogenicity. To overcome the relatively low immunogenicity of polysaccharide, PS vaccines are conjugated to protein carriers to increase immunogenicity and provide long-term protection in young children. Many meningococcal conjugate vaccines are already approved and marketed throughout the world. Examples of such vaccines, known as “Neisseria meningitidis conjugates” are monovalent meningococcal A conjugate (MenAfriVac), monovalent meningococcal C conjugate (Meningitec) and quadrivalent A C Y W meningococcal conjugates (Menveo & Menactra).
As well as being used for classification, the capsular polysaccharide has been used for vaccination. An injectable tetravalent vaccine of capsular polysaccharides from serogroups A, C, Y & W135 has been known for many years and is licensed for human use. Although effective in adolescents and adults, it induces a poor immune response and short duration of protection and cannot be used in infants. Mencevax ACWY™ and Menomune™ both contain 50 μg of each purified polysaccharide once reconstituted from their lyophilised forms. The capsular saccharides of serogroups A, C, W135 & Y have also been combined in the form of conjugates to give tetravalent vaccines e.g. the unadjuvanted Menactra™ product. Also conjugated serogroup A polysaccharide have been approved for human use as MenAfriVac™, serogroup C oligosaccharides have been approved for human use as Menjugate™, Meningitec™ and NeisVac-C™.
N. meningitidis serogroup X strains were first described in the 1960s and have been isolated from a few cases of invasive meningococcal diseases in North America, Europe, Australia, and China. Outbreaks of N. meningitidis serogroup X strains have been reported in Niger, western Kenya, and northern Ghana. N. meningitidis serogroup X strains were reported to be very efficient in colonization among military recruits in the United Kingdom. Refer Abdullah Kilic et al; Neisseria meningitidis Serogroup X Sequence Type 767 in Turkey; Journal Of Clinical Microbiology, November 2010, p. 4340-4341; Vol. 48, No. 11
It was reported that repeated mass vaccination in many African countries might have contributed to colonization by and meningococcal diseases due to serogroup X strains and might result in a changed profile of meningococcal disease Refer Gagneux, S. P et al; Prospective study of a serogroup X Neisseria meningitidis outbreak in northern Ghana. J. Infect. Dis. 185:618-626; 2002.
The capsular polysaccharides of serogroup B, C, Y, and W135 meningococci are composed of sialic acid derivatives. Serogroup B and C meningococci express (α 2-8)- and (α2-9 239)-linked polysialic acid, respectively, while alternating sequences of D-glucose or D-galactose and sialic acid are expressed by serogroup Y and W135 N. meningitidis. In contrast, the capsule of serogroup A meningococci is composed of (α 1-6)-linked N-acetylmannosamine 6-phosphate, while N. meningitidis serogroup X synthesizes capsular polymers of (α 1-4)-linked N-acetylglucosamine 1-phosphate. Refer Yih-Ling Tzeng et al; Genetic Basis for Biosynthesis of the (134)-Linked N-Acetyl-D-Glucosamine 1-Phosphate Capsule of Neisseria meningitidis Serogroup X; Infection And Immunity, December 2003, p. 6712-6720; Vol. 71, No. 12
The existing meningococcal conjugate vaccines are based on A C Y W135 polysaccharides. The increase in incidence of MenX disease in African Meningitis Belt in the last 5 years [1,4] warrants development and introduction of a MenX polysaccharide conjugate vaccine in selected areas of the region to prevent and control future epidemics. Though has been reported earlier. In spite of availability of comprehensive seroprevalence and structural data for meningococcal X, a commercially viable conjugate vaccine including X polysaccharide is yet to be developed due to extremely limited success on purification, conjugation and formulation stability aspects for the same. This provides an additional challenge for successfully addressing and controlling various parameters, especially when employing a scalable conjugation process for the large-scale manufacture of Neisseria meningitidis conjugates containing Neisseria meningitidis X polysaccharide.
The present invention arises from the surprising discovery that it is possible to prepare a monovalent or multivalent immunogenic composition based on conjugates of meningococcal polysaccharide from serogroup X by utilizing a scalable and efficient conjugation process.